A novel, RAS-independent role forNF1in microtubular dynamics and damage repair dictates sensitivity to T-DM1 in HER2-positive breast cancer

Abstract

AbstractThe gene neurofibromatosis 1 (NF1) is increasingly recognized as a key somatic driver of cancerogenesis, in addition to its well-known role as the germline determinant of the onco-developmental syndrome Neurofibromatosis. NF1 is best characterized as a negative regulator of RAS activation, but several lines of evidence suggest that it may have additional, poorly characterized functions.In breast cancer, NF1 loss is known to be associated with resistance to endocrine and HER2-targeted therapy. Here, using HER2+ breast cancer cell lines engineered to ablate NF1 by CRISPR-Cas9 and in vitro reductionist models, we show that NF1 is a bona fide Microtubule-Associated Protein (MAP) with a novel, RAS-independent role in regulating dynamic instability and intra-lattice repair of microtubules. We show that loss of NF1 results in multiple mitotic defects (enlarged mitotic plate, delayed mitotic exit, supranumerary centrosomes and chromosome misalignment) that generate a low-grade aneuploidy that can also be measured as increased aneuploidy score in breast cancer patients bearing pathogenic NF1 mutations. Loss of NF1 leads to increased sensitivity to the approved Antibody-Drug Conjugate T-DM1 and in particular to its payload of the maytansin family, thus representing the first payload-specific predictive biomarker.These findings highlight a novel function for an established tumor suppressor and support the assessment of NF1 status to guide tailored treatment decision in breast cancer